PHYSIOLOGIC ROLE OF CYTOKINES IN LIPOPOLYSACCHARIDE

腹膜腔内注射脂多糖(LPS)导致 许多急性期反应，包括发烧。它是 普遍认为，IP注射脂多糖可引起发热 内源性热原(EP)释放到循环中，如 白介素1、肿瘤坏死因子、白介素6、 或者其他的调解人。这些EP被认为作用于大脑以 提高温度调节设定值。循环中IL-1的作用 (以及在相当小的程度上，肿瘤坏死因子和白介素6)在发展中的作用 发烧已成为关于肺炎发病机制的中心教条的一部分。 发烧。由于一系列漂亮的间接实验 在过去的40年里支持这一假说的是 可以理解为什么几乎没有动力来评估这一点 更直接的假设。 然而，很有可能目前的许多回复 归因于IL-1或其他细胞因子将被证明是 “药理学的”而不是生理学或病理生理学的。这个 拟议的实验的目的是在 实验室大鼠，内毒素诱导的发烧实际涉及的程度 这些物质在循环和大脑中都有。这个 各种可能的内源性热原的鉴定、克隆 他们的特定基因，以及特异性和敏感度的发展 对它们的检测，现在允许对这些假设进行检验。

Intraperitoneal (ip) injection of lipopolysaccharide (LPS) results in many acute phase responses, including the development of fever. It is generally accepted that an ip injection of LPS induces fever by causing a release into the circulation of an endogenous pyrogen (EP), such as interleukin-1 (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6), or some other mediator. These EP's are thought to act on the brain to elevate the thermoregulatory set-point. The role of circulating IL-1 (and to a considerably lesser extent TNF and IL-6) in the development of fever has become part of the central dogma regarding the pathogenesis of fever. As a result of the beautiful sequence of indirect experiments that supported this hypothesis over the past 40 years, it is understandable why there has been little impetus to evaluate this hypothesis more directly. It is, however, quite possible that many of the responses currently attributed to IL-1 or to other cytokines will turn out to be "pharmacologic" rather than physiologic or pathophysiologic ones. The purpose of the proposed experiments is to evaluate critically, in the laboratory rat, the degree to which LPS-induced fever actually involves these substances both in the circulation and the brain. The identification of the various putative endogenous pyrogens, the cloning of their specific genes, and the development of specific and sensitive assays for them, now allow the testing of these hypotheses.